An elegant defense: how neutrophils shape the immune response
2009; Elsevier BV; Volume: 30; Issue: 11 Linguagem: Inglês
10.1016/j.it.2009.07.002
ISSN1471-4981
Autores Tópico(s)Immune cells in cancer
ResumoA key function of the immune system is to prevent the body's hostile takeover by microbes. Central to this host defense is the recognition and elimination of microbes. Neutrophils have long been recognized as the body's most important killers [1Kaufmann S.H. Immunology's foundation: the 100-year anniversary of the Nobel Prize to Paul Ehrlich and Elie Metchnikoff.Nat. Immunol. 2008; 9: 705-712Crossref PubMed Scopus (170) Google Scholar]. However, rather than being considered accurate snipers, neutrophils are often looked upon as crude and unrefined legionnaires, whose successful missions are often responsible for significant collateral damage [2Nathan C. Neutrophils and immunity: challenges and opportunities.Nat. Rev. Immunol. 2006; 6: 173-182Crossref PubMed Scopus (2047) Google Scholar]. Neutrophils are the first leukocyte to infiltrate inflamed tissue and the commands for their emigration are generated immediately after tissue injury, resulting in their rapid dispatch as an advance guard for subsequent immune cells. The neutrophil's most recognized function is to contain and clear infections. To do so, the neutrophil is armed with a variety of weapons allowing them to combat a broad range of microbes. Until relatively recently, the most studied antimicrobial functions employed by the neutrophil was engulfment, intracellular degradation, and the extracellular discharge of antimicrobial polypeptides (see Figure 1). In this regard an interesting new antimicrobial mechanism was identified in the shape of so-called ‘neutrophil extracellular traps’ (NETs). These are released from neutrophils following cell death and consist of decondensed chromatin embedded with granular and cytoplasmic proteins. In this themed issue of Trends in Immunology Papayannopoulos and Zychlinsky [3Papayannopoulos V. Zychlinsky A. NETs: a new strategy for using old weapons.Trends Immunol. 2009; 30: 513-521Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar] discuss the mechanisms underlying NET formation, their importance in innate immunity, and their potential implications in autoimmune disease. However, as will be highlighted in this special issue, viewing neutrophils as mere phagocytes and killers is now surely outdated. Research carried out over the last decade has updated our understanding of neutrophil behavior and revealed a hitherto unappreciated complexity.Granule contents are at the neutrophil's immediate command. Their mobilization instantly alters the neutrophil phenotype from a quiescent cell in flow to a highly responsive cell equipped with chemokine, cytokine, and pattern recognition receptors. Granule proteins released into the surroundings represent mediators that bind to specific receptors on nearby cells, allowing the rapid transmission of commands amongst various immune cells. Finally, emigrated neutrophils initiate a transcriptional burst leading to the release of cytokines, chemokines, as well as growth factors [4Borregaard N. et al.Neutrophil granules: a library of innate immunity proteins.Trends Immunol. 2007; 28: 340-345Abstract Full Text Full Text PDF PubMed Scopus (500) Google Scholar]. In this themed issue of Trends in Immunology we have gathered four articles focusing on the interplay between neutrophils and endothelial cells, monocytic cells, dendritic cells, and T cells.Inherent to inflammatory responses is an increase in vascular permeability, which in itself may lead to fatal consequences. DiStasi and Ley explain the mechanisms underlying neutrophil-mediated changes in vascular leakage [5DiStasi M.R. Ley K. Opening the flood-gates: how neutrophil-endothelial interactions regulate permeability.Trends Immunol. 2009; 30: 547-556Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar]. Central to these mechanisms are the release of preformed granule proteins (e.g. proteinase-3, azurocidin), secretion of cytokines and the direct neutrophil-endothelium interaction via ICAM-1 and E-selectin (Figure 1). Subsequent to the arrival of neutrophils, monocytes are recruited to the site of inflammation, a process at least partially mediated by neutrophil granule proteins [6Soehnlein O. et al.Neutrophil secretion products pave the way for inflammatory monocytes.Blood. 2008; 112: 1461-1471Crossref PubMed Scopus (294) Google Scholar]. The differentiation of monocytes towards macrophages as well as successive macrophage polarization is in part controlled by neutrophil granule proteins [7Soehnlein O. et al.Neutrophil primary granule proteins HBP and HNP1-3 boost bacterial phagocytosis by human and murine macrophages.J Clin Invest. 2008; 118: 3491-3502Crossref PubMed Scopus (150) Google Scholar]. Soehnlein et al. highlight mechanisms by which granule proteins command monocyte emigration as well as macrophage activation [8Soehnlein O. et al.Neutrophil granule protein tune monocytic cell function.Trends Immunol. 2009; 30: 511-512Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar]. Granule proteins, however, not only activate innate immunity, but also build a bridge to adaptive immunity. A structurally heterogeneous set of granule proteins termed alarmins are capable of mobilizing and activating dendritic cells, thus augmenting adaptive immune responses as emphasized in the article by Yang et al. [9Yang D. et al.Alarmins Link Neutrophils and Dendritic Cells.Trends Immunol. 2009; 30: 531-537Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar]. Besides neutrophil-derived alarmins, direct cell-cell interaction between neutrophils and immature dendritic cells as well as neutrophil secretion of TNFα is crucial for their ability to trigger dendritic cell maturation [10van Gisbergen K.P. et al.Close encounters of neutrophils and DCs.Trends Immunol. 2005; 26: 626-631Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar] (Figure 1). Finally, Muller et al. focus on the complex interaction between neutrophils and T cells [11Muller I. et al.Polymorphonuclear neutrophils and T lymphocytes: strange bedfellows or brothers in arms?.Trends Immunol. 2009; 30: 522-530Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar]. While trans-differentiated neutrophils acquire an antigen-presenting cell-like phenotype promoting their ability to activate T cells, neutrophil-derived arginase, reactive oxygen species, and nitric oxide suppress T cell function (Figure 1). Therefore depending on context, neutrophils are able to either potentiate or down-modulate T cell function.Knowledge of the kind provided in this themed issue may stimulate the pursuit and development of therapeutic interventions aimed at neutrophil-mediated immune activation. Therein, the question is no longer why or if, but rather how to target the innate immune system [12Brown K.L. et al.Complexities of targeting innate immunity to treat infection.Trends Immunol. 2007; 28: 260-266Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar]. Due to the redundancy of neutrophil-mediated cell activation by e.g. signals generated by proteases it has been difficult to neutralize individual granule proteins. However, it might be more promising to target receptors employed by granule proteins to activate endothelial cells, macrophages, and dendritic cells. In addition, inhibition of PMN degranulation in acute inflammatory processes may abolish over-zealous immune activation such as that seen during sepsis. While most researchers working on neutrophil-targeted therapies focus on anti-inflammatory strategies, it might be wise to also pursue alternate approaches. In this context, insight into neutrophil-macrophage interactions has recently led to the synthesis of a peptide that in its activity is reminiscent of defensins and the cathelicidin LL-37 [13Scott M.G. et al.An anti-infective peptide that selectively modulates the innate immune response.Nat Biotechnol. 2007; 25: 465-472Crossref PubMed Scopus (311) Google Scholar]. Despite the lack of direct antimicrobial effects, this peptide activates antimicrobial function in macrophages. Therefore decoding the complex interactions between neutrophils and cells of the innate and adaptive immune systems should hold great opportunities for creating specific and custom-made therapies with few side effects. Conclusively, research areas shedding light on the complex, redundant and finely balanced nature of the innate immune system shall warrant more attention. A key function of the immune system is to prevent the body's hostile takeover by microbes. Central to this host defense is the recognition and elimination of microbes. Neutrophils have long been recognized as the body's most important killers [1Kaufmann S.H. Immunology's foundation: the 100-year anniversary of the Nobel Prize to Paul Ehrlich and Elie Metchnikoff.Nat. Immunol. 2008; 9: 705-712Crossref PubMed Scopus (170) Google Scholar]. However, rather than being considered accurate snipers, neutrophils are often looked upon as crude and unrefined legionnaires, whose successful missions are often responsible for significant collateral damage [2Nathan C. Neutrophils and immunity: challenges and opportunities.Nat. Rev. Immunol. 2006; 6: 173-182Crossref PubMed Scopus (2047) Google Scholar]. Neutrophils are the first leukocyte to infiltrate inflamed tissue and the commands for their emigration are generated immediately after tissue injury, resulting in their rapid dispatch as an advance guard for subsequent immune cells. The neutrophil's most recognized function is to contain and clear infections. To do so, the neutrophil is armed with a variety of weapons allowing them to combat a broad range of microbes. Until relatively recently, the most studied antimicrobial functions employed by the neutrophil was engulfment, intracellular degradation, and the extracellular discharge of antimicrobial polypeptides (see Figure 1). In this regard an interesting new antimicrobial mechanism was identified in the shape of so-called ‘neutrophil extracellular traps’ (NETs). These are released from neutrophils following cell death and consist of decondensed chromatin embedded with granular and cytoplasmic proteins. In this themed issue of Trends in Immunology Papayannopoulos and Zychlinsky [3Papayannopoulos V. Zychlinsky A. NETs: a new strategy for using old weapons.Trends Immunol. 2009; 30: 513-521Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar] discuss the mechanisms underlying NET formation, their importance in innate immunity, and their potential implications in autoimmune disease. However, as will be highlighted in this special issue, viewing neutrophils as mere phagocytes and killers is now surely outdated. Research carried out over the last decade has updated our understanding of neutrophil behavior and revealed a hitherto unappreciated complexity. Granule contents are at the neutrophil's immediate command. Their mobilization instantly alters the neutrophil phenotype from a quiescent cell in flow to a highly responsive cell equipped with chemokine, cytokine, and pattern recognition receptors. Granule proteins released into the surroundings represent mediators that bind to specific receptors on nearby cells, allowing the rapid transmission of commands amongst various immune cells. Finally, emigrated neutrophils initiate a transcriptional burst leading to the release of cytokines, chemokines, as well as growth factors [4Borregaard N. et al.Neutrophil granules: a library of innate immunity proteins.Trends Immunol. 2007; 28: 340-345Abstract Full Text Full Text PDF PubMed Scopus (500) Google Scholar]. In this themed issue of Trends in Immunology we have gathered four articles focusing on the interplay between neutrophils and endothelial cells, monocytic cells, dendritic cells, and T cells. Inherent to inflammatory responses is an increase in vascular permeability, which in itself may lead to fatal consequences. DiStasi and Ley explain the mechanisms underlying neutrophil-mediated changes in vascular leakage [5DiStasi M.R. Ley K. Opening the flood-gates: how neutrophil-endothelial interactions regulate permeability.Trends Immunol. 2009; 30: 547-556Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar]. Central to these mechanisms are the release of preformed granule proteins (e.g. proteinase-3, azurocidin), secretion of cytokines and the direct neutrophil-endothelium interaction via ICAM-1 and E-selectin (Figure 1). Subsequent to the arrival of neutrophils, monocytes are recruited to the site of inflammation, a process at least partially mediated by neutrophil granule proteins [6Soehnlein O. et al.Neutrophil secretion products pave the way for inflammatory monocytes.Blood. 2008; 112: 1461-1471Crossref PubMed Scopus (294) Google Scholar]. The differentiation of monocytes towards macrophages as well as successive macrophage polarization is in part controlled by neutrophil granule proteins [7Soehnlein O. et al.Neutrophil primary granule proteins HBP and HNP1-3 boost bacterial phagocytosis by human and murine macrophages.J Clin Invest. 2008; 118: 3491-3502Crossref PubMed Scopus (150) Google Scholar]. Soehnlein et al. highlight mechanisms by which granule proteins command monocyte emigration as well as macrophage activation [8Soehnlein O. et al.Neutrophil granule protein tune monocytic cell function.Trends Immunol. 2009; 30: 511-512Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar]. Granule proteins, however, not only activate innate immunity, but also build a bridge to adaptive immunity. A structurally heterogeneous set of granule proteins termed alarmins are capable of mobilizing and activating dendritic cells, thus augmenting adaptive immune responses as emphasized in the article by Yang et al. [9Yang D. et al.Alarmins Link Neutrophils and Dendritic Cells.Trends Immunol. 2009; 30: 531-537Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar]. Besides neutrophil-derived alarmins, direct cell-cell interaction between neutrophils and immature dendritic cells as well as neutrophil secretion of TNFα is crucial for their ability to trigger dendritic cell maturation [10van Gisbergen K.P. et al.Close encounters of neutrophils and DCs.Trends Immunol. 2005; 26: 626-631Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar] (Figure 1). Finally, Muller et al. focus on the complex interaction between neutrophils and T cells [11Muller I. et al.Polymorphonuclear neutrophils and T lymphocytes: strange bedfellows or brothers in arms?.Trends Immunol. 2009; 30: 522-530Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar]. While trans-differentiated neutrophils acquire an antigen-presenting cell-like phenotype promoting their ability to activate T cells, neutrophil-derived arginase, reactive oxygen species, and nitric oxide suppress T cell function (Figure 1). Therefore depending on context, neutrophils are able to either potentiate or down-modulate T cell function. Knowledge of the kind provided in this themed issue may stimulate the pursuit and development of therapeutic interventions aimed at neutrophil-mediated immune activation. Therein, the question is no longer why or if, but rather how to target the innate immune system [12Brown K.L. et al.Complexities of targeting innate immunity to treat infection.Trends Immunol. 2007; 28: 260-266Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar]. Due to the redundancy of neutrophil-mediated cell activation by e.g. signals generated by proteases it has been difficult to neutralize individual granule proteins. However, it might be more promising to target receptors employed by granule proteins to activate endothelial cells, macrophages, and dendritic cells. In addition, inhibition of PMN degranulation in acute inflammatory processes may abolish over-zealous immune activation such as that seen during sepsis. While most researchers working on neutrophil-targeted therapies focus on anti-inflammatory strategies, it might be wise to also pursue alternate approaches. In this context, insight into neutrophil-macrophage interactions has recently led to the synthesis of a peptide that in its activity is reminiscent of defensins and the cathelicidin LL-37 [13Scott M.G. et al.An anti-infective peptide that selectively modulates the innate immune response.Nat Biotechnol. 2007; 25: 465-472Crossref PubMed Scopus (311) Google Scholar]. Despite the lack of direct antimicrobial effects, this peptide activates antimicrobial function in macrophages. Therefore decoding the complex interactions between neutrophils and cells of the innate and adaptive immune systems should hold great opportunities for creating specific and custom-made therapies with few side effects. Conclusively, research areas shedding light on the complex, redundant and finely balanced nature of the innate immune system shall warrant more attention. This work was supported by the Deutsche Forschungsgemeinschaft (SO876/3-1, FOR809) and the German Heart Foundation/German Foundation of Heart Research.
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